Due to their volatility and their olfactory properties, aldehydes constitute important active ingredients in fragrance and flavour applications (a) C. Chapuis, D. Jacoby, Appl. Catal. A: Gen. 2001, 221, 93-117; b) D. Pybus, C. Sell, The chemistry of fragrances, RSC Paperbacks, Royal Society of Chemistry, Cambridge, 1999). Since the enantiomers of α- and β-substituted aldehydes often considerably differ in odour (a) A. Abate, E. Brenna, C. Fuganti, F. G. Gatti, S. Serra, Chem. Biodivers. 2004, 1, 1888-1898; b) L. Doszczak, P. Kraft, H.-P. Weber, R. Bertermann, A. Triller, H. Hatt, R. Tacke, Angew. Chem. Int. Ed. 2007, 46, 3367-3371; c) E. Brenna, C. Fuganti, S. Serra, Tetrahedron: Asymmetry 2003, 14, 1-42), their application in nonracemic form is often required. Whereas β-substituted aldehydes are chirally stable, α-substituted analogues are prone to racemisation, which requires sophisticated methods for their preparation. Among them, the desymmetrisation of conjugated enals via asymmetric hydrogenation is the method of choice (L. A. Saudan, Acc. Chem. Res. 2007, 40, 1309-1319). Whereas numerous protocols using chirally modified homogeneous (transition-metal) containing catalysts have been reported (For example see: a) S. Akutagawa, Appl. Catal. A: Gen. 1995, 128, 171-207; b) S. Bovo, A. Scrivanti, M. Bertoldini, V. Beghetto, O. Matteoli, Synthesis 2008, 2547-2550; c) W. S. Knowles, R. Noyori, Acc. Chem. Res. 2007, 40, 1238-1239; d) A. J. Minnaard, B. L. Fering a, L. Lefort, J. G. de Vries, Acc. Chem. Res. 2007, 40, 1267-1277), metal-independent organocatalysts for the reduction of enals at the expense of a nicotinamide-mimic (‘Hantzsch-ester’) as hydride source were developed more recently (a) J. W. Yang, M. T. H. Fonseca, N. Vignola, B. List, Angew. Chem. Int. Ed. 2005, 44, 108-110; b) H. Adolfsson, Angew. Chem. Int. Ed. 2005, 44, 3340-3342; c) S. G. Ouellet, A. M. Walji, D. W. C. MacMillan, Acc. Chem. Res. 2007, 40, 1327-1339; d) K. Akagawa, H. Akabane, S. Sakamoto, K. Kudo, Tetrahedron: Asymmetry 2009, 20, 461-466). To date, chirally surface-modified heterogeneous catalysts are not competitive (a) D. J. Watson, R. J. B. R. J. Jesudason, S. K. Beaumont, G. Kyriakou, J. W. Burton, R. M. Lambert, J. Am. Chem. Soc. 2009, 131, 14584-14589; b) A. Tungler, E. Sipos, V. Hada, Curr. Org. Chem. 2006, 10, 1569-1583). As an alternative to the variety of chemo-catalytic methods, bio-reduction has been envisaged by using various types of redox enzymes (S. Serra, C. Fuganti, E. Brenna, Trends Biotechnol. 2005, 23, 193-198). In order to circumvent tedious protein purification and external cofactor-recycling, whole microbial cells—most prominent baker's yeast—were employed for the reduction of enals. Due to the presence of competing ene- and carbonyl-reductases, the chemo- and stereoselective bioreduction of enals was impossible, since undesired carbonyl reduction always overruled the desired C═C-bond reduction, thereby causing substrate- and product-depletion via formation of the corresponding allylic and/or saturated alcohols (a) M. Majeric, A. Avdagic, Z. Hamersak, V. Sunjic, Biotechnol. Lett. 1995, 17, 1189-1194; b) C. Fuganti, S. Serra, J. Chem. Soc. Perkin Trans. 1, 2000, 3758-3764; c) P. D'Arrigo, C. Fuganti, G. Pedrocchi-Fantoni, S. Servi, Tetrahedron 1998, 54, 15017-15026; d) G. Fronza, C. Fuganti, P. Grasselli, L. Majori, G. Pedrocchi-Fantoni, F. Spreafico, J. Org. Chem. 1982, 47, 3289-3296; e) G. Fronza, C. Fuganti, M. Pinciroli, S. Serra, Tetrahedron: Asymmetry 2004, 15, 3073-3077; f) V. Sunjic, M. Majeric, Z. Hamersak, Croat. Chem. Acta 1996, 69, 643-660).
It was only recently, that oxygen-stable ene-reductases from the Old Yellow Enzyme family became available in sufficient amounts, which allowed the chemo- and stereoselective bioreduction of activated C═C-bonds in enones and enals by leaving C═O-moieties untouched (for a review see: a) R. Stuermer, B. Hauer, M. Hall, K. Faber, Curr. Opin. Chem. Biol. 2007, 11, 203-213; b) S. K. Padhi, D. J. Bougioukou, J. D. Stewart, J. Am. Chem. Soc. 2009, 131, 3271-3280; c) J. F. Chaparro-Riggers, T. A. Rogers, E. Vazquez-Figueroa, K. M. Polizzi, A. S. Bommarius, Adv. Synth. Catal. 2007, 349, 1521-1531; d) M. Kataoka, A. Kotaka, R. Thiwthong, M. Wada, S, Nakamori, S. Shimizu, J. Biotechnol. 2004, 114, 1-9. For the stereoselective bioreduction of α-methylcinnamaldehyde see: A. Müller, B. Hauer, B. Rosche, Biotechnol. Bioeng. 2007, 98, 22-29). Encouraged by our recent results (a) M. Hall, C. Stueckler, W. Kroutil, P. Macheroux, K. Faber, Angew. Chem. Int. Ed. 2007, 46, 3934-3937; b) M. Hall, C. Stueckler, H. Ehammer, E. Pointner, G. Oberdorfer, K. Gruber, B. Hauer, R. Stuermer, W. Kroutil, P. Macheroux, K. Faber, Adv. Synth. Catal. 2008, 350, 411-418; c) M. Hall, C. Stueckler, B. Hauer, R. Stuermer, T. Friedrich, M. Breuer, W. Kroutil, K. Faber, Eur. J. Org. Chem. 2008, 1511-1516), we investigated the application of these enzymes for the preparation of nonracemic α-methyl dihydrocinnamaldehyde derivatives used in perfumery applications (for the stereoselective bioreduction of α-methylcinnamaldehyde see: A. Müller, B. Hauer, B. Rosche, Biotechnol. Bioeng. 2007, 98, 22-29).
There is still a need for improved enzymatic methods of preparing enantiomeric forms of alpha-substituted aromatic aldehydes.